Although Smallpox no longer naturally circulates it remains a potential threat as a biological weapon. Currently, Smallpox is listed as the most important viral bioweapon by the United States. As a result, in 2001, the US resumed smallpox vaccinations for first responders (eg. ER personnel) and the military. The Smallpox vaccine, Vaccinia virus, is a live attenuated virus and adverse vaccine responses are common. In addition, outbreaks of animal pox viruses occasionally occur in humans. There is a possibility that infection of the eye with ensuing conjuncitivitis and keratitis, and perhaps blinding disease, can occur either following vaccination or zoonotic transfer . Virtually nothing is known about pathological mechanisms involved in Vaccinia ocular infections or other poxvirus ocular infections. Previously we developed a quantitative rabbit model of Vaccinia virus keratitis and we showed that the inclusion of topical steroids in therapy was potentially dangerous. In all groups that received prednisolone, keratitis rebounded within 3-4 days of halting the treatment and this was concomitant with the resumption of viral replication. Mouse models are much more suitable for studies on pathology and immunology of Vaccinia infections because of reagent availability. Therefore, the goal of this R21 application is to develop a novel quantitative mouse model of Vaccinia virus ocular infection. PUBLIC HEALTH RELEVANCE: The Smallpox vaccine, Vaccinia virus, is a live attenuated virus and adverse vaccine responses are common. In addition, outbreaks of animal pox viruses occasionally occur in humans. Virtually nothing is known about pathological mechanisms involved in Vaccinia ocular infections or other poxvirus ocular infections. Mouse models are much more suitable for studies on pathology and immunology of Vaccinia infections, thus the goal is to develop a novel quantitative mouse model of Vaccinia virus ocular infection.